14 Metformin (S24E14)

You know, it's easy to think our modern medicine
is just sort of appeared fully formed. Right.
But the reality is often this amazing long journey,
centuries sometimes. Did you know some of today's
treatments have roots way back in the Middle
Ages? It's wild. It really is. OK, let's unpack
this, because in this deep dive, we're focusing
on metformin. I mean. It's a super common drug
for type 2 diabetes. Oh, absolutely. But it's
so much more than just a daily pill for many
people. The story behind it connects traditional
medicine, how we understand diabetes, and some
really surprising twists. Exactly. And that's
what we really want to explore with you today.
We're not just going to cover what metformin
does right now. We'll dig into its, well, surprisingly
old origins, trace how science figured it out,
understand how it actually works in your body,
and even touch on some regulatory hurdles and
its wider impact. Yeah, the goal is really to
give you a clear, kind of insightful picture
of this drug. So you feel properly informed,
but hopefully not bogged down in technical stuff.
Right. And to do that, we've looked at, well,
a whole range of things. We have scientific reports
on the mechanisms, clinical reviews on how well
it works, historical accounts, manufacturing
info. even cultural perspectives on managing
diabetes. It's a multifaceted approach, hoping
to give a really rich understanding. Hopefully.
So where does this whole story kick off? It's
pretty amazing, actually. We have to go way back.
Middle ages kind of back. Yeah, to a plant called
Gallega officinalis. Goats roe, right. Or French
lilac. That's the one. Traditional healers back
then noticed it seemed to help with symptoms
we now link to diabetes, like frequent urination.
And this folk knowledge persisted for hundreds
of years. It did. Then, fast forward to the early
20th century, scientists started asking, OK,
what in this plant is doing this? And they found
compounds called guanidines. Yeah, a critical
finding. They saw guanidine could lower blood
glucose. Big problem, though. It's too toxic.
Exactly. Too toxic for widespread safe use in
people. OK, so back to the drawing board. Sort
of. They looked for safer things in the plant.
Right. And by 1923, they'd identified a less
toxic relative called galagene. Isoamaline guanidine,
technically. And early human studies looked promising.
They did. It lowered blood sugar in diabetics,
but didn't really affect people with normal blood
sugar much. OK, here's where it gets really interesting,
though. Because around the same time, 1922, actually,
chemists Werner and Bell synthesized metformin
itself. 11 -dimethyl big one -eyed. But... And
this is a key point. Even though they made it
early on, it wasn't the focus. Why not? Well,
the attention initially went to other related
compounds, other biguanides, specifically finformin
and buformin. Ah, because they seem stronger,
more potent, glucose lower. They seem to have
a more powerful effect, yeah. So for a while,
metformin was kind of forgotten, pushed aside
because these others looked more promising. Wow.
Shows how research can take different paths.
But something brought biguanides back. It did,
and kind of accidentally. During World War II,
a big one -eyed being tested for malaria. No
way. Yeah, it was found to have a side effect
of lowering blood glucose. Huh, so that's Birdmoor
research. It inspired a French doctor, Jean Stern,
to look specifically at metformin again, but
this time for what they called adult -onset diabetes
back then. And his work was key. Absolutely crucial.
In the late 50s, 57, 58, he published studies
showing metformin worked. It lowered blood glucose
effectively in type 2 diabetes. And crucially,
without the big risks. Right. Without causing
hypoglycemia, that dangerous low blood sugar,
or the lactic acidosis buildup that was becoming
a concern with finformin and buformin in some
studies. So that safety profile was the big difference.
It seemed to be. Based on his early work. And
that led to metformin being introduced in the
UK and other parts of Europe, starting in 1958.
But, and this might surprise people, it took
ages to get approved in the U .S. It did. Not
until 1994 for FDA approval, and it hit the market
there in 95. Why the long delay? Mostly lingering
concerns. Worries about lactic acidosis and maybe
cardiovascular effects, largely based on the
negative experiences with those other big one
-eyed sinformin and metformin. Right. So the
history of the whole drug class kind of cast
a shadow. It really shows how rigorous and sometimes
slow the regulatory process can be and how past
experiences, good and bad, influence things.
OK, so quite a backstory to become the standard
it is today. Speaking of which, let's get into
its clinical uses now. I mean, it's fundamental
for type 2 diabetes treatment. Oh, absolutely.
It's the recommended first line therapy for most
people diagnosed with P2DM and for very good
reasons. Its main job is lowering blood sugar,
right? Both fasting and after meals. Correct.
It lowers both your basal or fasting glucose
and your post cranial glucose, the spike after
you eat. It does this in a few ways. The liver
is a big part of it. That's the main one, yes.
It works primarily by inhibiting the liver's
production of glucose. That process is called
gluconeogenesis. So it tells the liver's backup
glipose factory to slow down production. That's
a good way to put it. But it also helps in other
ways. It reduces how much glucose you absorb
from your food in the gut. OK. And it improves
how your body's cells, especially muscle cells,
respond to insulin and take up glucose from the
blood. And a key point you mentioned earlier,
when used alone for type 2 diabetes, it generally
doesn't cause hypoglycemia. That's a major advantage,
yeah. Unlike some other diabetes drugs, the risk
of dangerously low blood sugar is very low with
metformin monotherapy. And the benefits seem
to go beyond just sugar control. We hear about
weight, maybe lipids. That's right. Research
suggests it can contribute to modest weight reduction,
or at least weight neutrality, which is helpful.
It can also help improve lipid profiles, lowering
LDL cholesterol and triglycerides. And there's
evidence suggesting it plays a role in preventing
vascular complications. Thinking about bigger
studies. The UK PDS comes to mind. Yes. The UK
perspective diabetes study back in 1998 was landmark.
It provided strong evidence that metformin not
only improved glucose control, but also reduced
the risk of cardiovascular disease and death
from any cause, particularly in overweight patients.
This was seen in those with normal or only mildly
reduced kidney function at the time. And newer
studies seem to back this up. They do. For instance,
the RIAC Italian study from 2013 suggested metformin
was linked to a lower rate of cardiovascular
disease across different age groups and different
levels of kidney function compared to other diabetes
treatments. OK, that brings up the kidney function
point. That's been a bit of a moving target,
hasn't it? It has. For a long time, there was
a lot of caution, even contraindication, for
using metformin if someone had kidney problems
because of that lactic acidosis concern. Right.
But that thinking has shifted. Yes. Significantly.
Current guidelines now generally recommend that
metformin can often be continued, although maybe
at a reduced dose, in patients with moderate
kidney impairment. We're talking a GFR, that
measure of kidney filtration, between 30 and
59 milliliters per minute. And the rationale
for that change? Well, there are a couple things.
One is recognizing that stopping metformin might
mean losing its pinchual cardiovascular benefits
in a group already at higher risk. Okay. And
two, switching to alternatives like insulin or
sulfonylureas might actually increase the risk
of other problems, particularly hypoglycemia.
That makes sense, weighing the different risks.
Exactly. There was even one retrospective study
in 2015 looking at patients with severe stage
five kidney disease who were on specific anemia
drugs. Even though metformin was technically
contraindicated, the patients in that study who
were taking it didn't show a statistically significant
increase in metabolic acidosis risk compared
to those who weren't. Interesting. But still
caution needed. Oh, definitely. The guidelines
still generally say stop metformin if the GFR
drops below 30. The risk does increase with more
severe kidney disease, but it highlights this
evolving picture and the need for individual
assessment. It's not just for established diabetes,
either. What about pre -diabetes? Yes, that's
another area. Several big analyses in the American
Diabetes Association suggest metformin can be
considered alongside lifestyle changes, of course.
Lifestyle first, though. Lifestyle is definitely
more effective and the primary recommendation.
But metformin might be an option to help lower
the risk of progressing to full type 2 diabetes,
especially for certain people, maybe those under
60. those with a very high BMI, or women with
a history of gestational diabetes. And the research
story continues, looking beyond type 2. Right.
There are several emerging areas that are quite
exciting, actually. Like what? Well, gestational
diabetes, for one. Some studies, like ones from
Canada and Australia, suggest metformin can lead
to better glucose control during pregnancy, reduce
the need for insulin injections, and maybe even
lower the rate of C -sections compared to placebo
or insulin. Are there any downsides there? There
are some considerations. Some studies noted potentially
lower birth weights and maybe a slightly higher
chance of babies being born small for their gestational
age. So it's still being actively studied and
discussed. What else? Type 1 diabetes. Potentially
as an add -on therapy for people with type 1
who are also overweight or obese. The idea is
to help manage the insulin resistance that can
sometimes develop alongside type 1. And then
there's the cancer connection we sometimes hear
about. Yes, that's a huge area of research. Right
now, large reviews haven't definitively concluded
that metformin reduces overall cancer risk across
the board. The results are a bit mixed, maybe
inconclusive. But research is ongoing. Very much
so. Scientists are looking at its effects on
specific types of tumors. in specific tissues,
and even in rare genetic syndromes, like live
from any, that dramatically increase cancer risk.
And probably the most talked about potential
use? Aging? Ah yes, the anti -aging potential.
There's a lot of buzz around that. What's the
thinking there? Well, studies in model organisms,
like the tiny, warm C. elegans, show metformin
seems to influence several fundamental pathways
linked to aging. Like what kind of pathways?
Things like insulin signaling, a major growth
pathway called MTOR, the function of mitochondria,
that sells powerhouses, an energy sensor called
AMPK. It also seems to reduce oxidative stress,
DNA damage, inflammation. Wow, that's a lot.
It is. It also impacts processes like autophagy,
which is cellular cleanup, and cellular senescence,
sort of like cell aging. It even affects the
gut microbes in worms, though we don't have clear
evidence for that specific effect in humans yet.
So the idea is it might gently nudge these core
aging processes in a healthier direction? That's
the hope, based on these preclinical studies.
Obviously, translating that to humans is a whole
other ballgame, and large clinical trials like
TAME targeting aging with metformin, are designed
to investigate this. Fascinating. It sounds like
this old drug might still have some new tricks.
So let's get into the nitty -gritty of how it
works. The mechanism. Okay, so as we said, the
main glucose lowering effect is shutting down
excess glucose production in the liver inhibiting
gluconeogenesis. But there are indirect things
happening too. Yes, it's becoming clear that
indirect effects contribute significantly. For
instance, fat breakdown in adipose tissue releases
glycerol and fatty acids. Which can fuel glucose
production in the liver. Exactly. And while metformin's
direct effect on fat cells isn't its main job,
the overall improvement in insulin sensitivity
it causes can indirectly influence these processes.
Its main side of action, where it really accumulates
and works, is the liver. Right. Now when you
take a metformin pill, how much actually gets
into your system? The oral bioavailability is
around 50 to 60 percent. So about half of it
gets absorbed. Where does that happen? Primarily
in the small intestine. From there, it enters
the bloodstream and goes straight to the liver
via the portal vein. And then it spreads out.
Then it gets distributed to other tissues like
muscle and fat, where it helps them become more
sensitive to insulin and take up glucose more
effectively. How does your body get rid of it?
Does it get broken down? No, that's interesting.
It's not metabolized. It's excreted unchanged
by the kidneys. They actively secrete it into
the urine through tubules. That's the main way
out. Okay. And you mentioned the gut microbiota
earlier. Yes. That's a relatively newer area
of understanding. Research increasingly suggests
metformin significantly alters the composition
and function of the gut bacteria. And that might
contribute to how it works. It might. It could
contribute to both the glucose lowering effects
and potentially some of the common gastrointestinal
side effects people experience, like diarrhea
or nausea. Right, those are fairly common. Now
we see different versions, like geofage versus
geolucophage XR. What's the deal there? Okay,
so geolucophage is the standard immediate release
IR version. The drug gets released pretty quickly
after you swallow the pill. And XR. extended
release. Exactly. Geoleucaphage XR is designed
to release the medication more slowly over a
longer period. What difference does that make
in the body? It generally means you get a lower
peak concentration of the drug in your blood
that's called C -max, and it takes longer to
reach that peak that's T -max compared to the
immediate release. But you still absorb the same
total amount. Pretty much yes. The overall absorption,
we call the AUC, or area under the curve, is
similar if you compare equivalent daily doses.
Like, 2 ,000 milligrams of XR once daily gives
similar total exposure to 1 ,000 milligrams of
IR twice daily. And it doesn't build up over
time with the XR. Studies suggest it doesn't
accumulate in the plasma with repeated XR dosing,
which is good. The idea behind XR is often to
improve gastrointestinal tolerance and allow
for once daily dosing. So a smoother ride, potentially
fewer side effects for some people. That's the
aim. We also saw GL -U -METS I mentioned. Is
that another type of XR? It is, yes. It's another
modified release formulation, but it uses a different
delivery technology involving polymers to release
the drug primarily in the upper GI tract. Different
mechanism, same goal of slower release. Does
the way the body handles metformin change much
with age or, say, kidney problems? It can, yes.
In older adults, studies generally show that
metformin clearance decreases, the body gets
rid of it more slowly, the half -life might be
longer, and the P concentration could be higher
compared to younger folks. Mostly due to kidney
function declining with age. Primarily, yes.
Age -related changes in renal function are the
main driver. And as we discussed, in people with
diagnosed renal impairment, the pharmacokinetics
definitely change depending on the severity.
Oh, so. As kidney function, GFR goes down, the
drug tends to stick around longer peak levels,
CMACs get higher, and total exposure, AUC, increases
because the kidneys just can't clear it as efficiently.
There are specific tables showing how these parameters
change across different stages of kidney disease.
And liver problems. Interestingly, there haven't
been specific pharmacokinetic studies in people
with hepatic insufficiency. So we don't have
clear data on how liver problems affect metformin
handling. OK. What about drug interactions, things
people should be careful about taking alongside
metformin? Absolutely, that's important. Certain
drugs can increase the risk of that rare, but
serious side effect, metformin -associated lactic
acidosis. Which drugs are we talking about? Generally,
drugs that can also impair kidney function, cause
major changes in blood pressure or circulation,
mess with the body's acid -base balance, or directly
interfere with metformin elimination, causing
it to build up. Can you give an example? Sure.
Nectartine, a calcium channel blocker used for
blood pressure, has been shown to slightly increase
metformin Cmax and AUC. More significantly, drugs
that inhibit specific transporters in the kidney
tubules responsible for secreting metformin.
OCT2 and MADI transporters. Exactly. Inhibitors
of those, like the anti -anginal drug Ranolazine,
some cancer drugs like Vandetanib, the HIV drug
Dilute Gravir, and the older heartburn medication,
Semetidine. These can reduce metformin clearance.
And that increases risk. Potentially, yes, by
causing metformin levels to rise. The interaction
with smedidine was quite significant in studies.
It caused about a 60 % increase in peak metformin
concentration and a 40 % increase in total exposure.
Wow, so definitely important for doctors and
pharmacists to check for these interactions.
Crucial. Always need that complete medication
list. Okay, switching gears slightly. How is
this stuff actually made? It's easy to just see
the pill. Yeah, the manufacturing is quite large
scale. One source, a document about an API active
pharmaceutical ingredient manufacturing plant.
So making the raw drug powder. Right. It mentioned
storing metformin hydrochloride solid in bags
or drums with a potential site capacity of like
100 metric tons. Gives you a sense of the volume.
That's a lot. And then making the actual tablets,
like those combination pills. Right. For something
like Acto Plus Met XR. which combines metformin
with another drug, pioglitazone, it uses specialized
tech. They mentioned a scoit system single -composition
osmotic tablet. What does that mean? It means
they create an extended release core containing
the metformin, and then they coat that core with
an immediate release layer of the other drug,
the pioglitazone. Clever, like a layered approach
in one pill. Exactly, and we also saw a study
looking at the process validation for standard
metformin -sustained release tablets. What did
that involve? Making sure the process works consistently.
Pretty much. It detailed the steps, dry mixing
the ingredients, adding lubricants so the powder
flows, compressing it into tablets and packaging.
But crucially, it detailed all the quality control
checks. Like what? Checking the assay is the
right amount of drug there. Content uniformity
does each tablet have the same dose. Physical
checks, size, shape, hardness they need to be
strong enough, friability they shouldn't crumble
easily, and dissolution testing. how quickly
the drug releases. Right. Does it release over
time as expected in the lab test that mimics
the body? They had specific acceptance criteria,
like hardness needed to be at least 5 kg in the
loss, friability no more than 1 % loss, and dissolution
releasing at least 80 % by a certain time point.
So lots of checks along the way. Rigorous quality
control is essential. Absolutely baked into the
process. Now, let's talk regulation and maybe
controversy. Metformin's been around, but the
regulatory view has evolved, right? Especially
around lactic acidosis. It really has. The European
Medicines Agency, the EMA, put out a report in
2016 specifically looking at this. They revised
the guidance for using metformin in kidney impairment,
as we discussed. And they noted the risk seemed
lower than previously thought. Yes, they highlighted
that the risk of fatal lactic acidosis seemed
to have declined over time, from maybe around
50 % in older data down to less than 20 % more
recently. And the cause wasn't always just the
metformin itself. That's what recent studies
increasingly suggest. Lactic acidosis, when it
happens in people taking metformin, is often
strongly linked to underlying acute conditions.
Things like shock, severe heart failure, sepsis,
acute kidney injury. One study found a very high
association, like a 9 .5 times higher odds, with
acute kidney injury. So metformin might be present,
but another serious illness is often the main
driver. That seems to be the current understanding,
which has led agencies like the one in Malta,
for example, to officially update guidelines
allowing use in moderate kidney disease, GFR.
3059, with dose adjustments and monitoring, while
still keeping it contraindicated below a GFR
of 30. But more recently, there's been another
regulatory headache. Impurities. Ah, yes, the
nitrosamine issue. That definitely made headlines.
And DMA, right. And nitricidamethylamine, yes.
Finding this potential carcinogen as an insurity
in some batches of metformin products led to
significant concerns and recalls. In the U .S.
and elsewhere. Yes. Regulatory agencies like
the FDA and also independent labs like Valizier
flag this, leading to voluntary recalls by manufacturers
for affected lots. And this links back to things
like that AARP article mentioning recalls due
to cancer risk. Exactly. It became a major safety
focus, prompting tighter controls and testing
for these types of impurities in manufacturing.
It's a reminder that even for very old established
drugs, ongoing vigilance is critical. It really
is. A wake up call about continuous monitoring.
Okay, finally, let's think about the big picture
economic impact cultural aspects. It's huge globally,
right? Economically, its impact is massive. Being
an inexpensive, widely available first -line
treatment for over 60 years makes it a cornerstone
of diabetes management globally, saving health
care systems vast amounts compared to newer,
often more expensive options. The market must
be enormous. It is. The fact that specialized
market research reports exist just for metformin
tells you how significant it is economically.
And culturally. Managing diabetes isn't just
clinical, is it? Not at all. Cultural beliefs
and practices play a huge role. Providing culturally
competent care is so important. There are even
communication models designed to help doctors
understand a patient's background and beliefs
about their illness. Things like ESFT, ethnic
learn models. Can you give an example? Sure.
Some American Indian tribes, for instance, might
have specific cultural beliefs about why diabetes
occurs, maybe related to external influences
or changes in traditional ways. And understanding
that can affect how treatment recommendations
are received. Some tribal programs actively promote
traditional diets as part of diabetes management.
That makes sense. Or managing insulin during
fasting periods. Exactly. Like during Ramadan.
People need to adjust their insulin regimens
carefully to avoid hypoglycemia while fasting.
This often leads to preferring specific types
of insulin, like basal and rapid -acting analogs,
that fit better with those cultural and religious
practices. It's a clear intersection of culture,
belief, and medical necessity. And even the formulation
matters. You mentioned a liquid version. Yes,
RailMet ER, the Extended Release Oral Suspension.
For people who have difficulty swallowing pills,
which could be common in older adults or people
with certain conditions, having a liquid option
can make a huge difference in their ability and
willingness to take the medication consistently.
It addresses a practical barrier that can have
cultural dimensions too. It's truly incredible.
A single molecule, discovered almost by accident
from a traditional remedy, becomes this global
mainstay with such a complex story. It really
is. From folk medicine, through decades of science,
regulatory shifts, manufacturing challenges,
and now exploring potential new roles in aging
and cancer, the former's journey is far from
over. So as we wrap up this deep dive, what's
a final thought for our listeners to chew on?
Well, maybe consider this. Given mitformin's
incredibly long history and widespread use, how
might research keep surprising us? Will we find
completely new uses for it or will we continue
to refine how we use it based on things like
genetic profiles or gut microbiome analysis?
Or maybe thinking about the nitrosamine issue.
What does that experience tell us about the ongoing
challenge of ensuring drug safety and quality,
even for medications we think we know inside
out after decades of use? It certainly highlights
the dynamic nature of medicine and regulation,
and hopefully it underscores the value of being
informed and having those good conversations
with your health care team about what's right
for you. Maybe this dive sparked some curiosity
to look deeper into the research or even the
cultural side of health in your own community.